This invention relates to a process for the preparation of pergolide, which utilizes 9,10-dihydrolysergol as a starting material. This process is a three-step synthesis procedure which involves acylation-dealkylation, reduction and sulfide formation. Pergolide can be obtained from 9,10-dihydrolysergol by either conducting acylation-dealkylation before sulfide formation in the procedure or vise versa.
Pergolide is a well-known drug particularly useful for the treatment of Parkinson""s disease. U.S. Pat. No. 4,166,182, issued to Kornfeld and Bach on Aug. 28, 1979, assigned to Eli Lilly and Company, first discloses pergolide and its derivatives, their pharmaceutical use, and a 7-step synthesis of pergolide starting from 9,10-dihydrolysergic acid. The 7-step process is shown in Scheme I: 
Since this process is too complex and not economically effective, improvements for the synthesis of pergolide have been studied and developed. U.S. Pat. No. 5,463,060, issued on Oct. 31, 1995 to Misner, assigned to Eli Lilly and Company, discloses a one-pot process for preparing pergolide from 9,10-dihydrolysergol (8,9-dihydroelymoclavine, as referred to in U.S. Pat. No. 5,463,060). The starting material, 9,10-dihydrolysergol, reacts first with 1-iodopropane, followed by sulfonyl halide, and an alkali metal thiomethoxide to give pergolide without isolating intermediate products, as shown in Scheme II: 
The present invention provides a novel process for the preparation of pergolide from 9,10-dihydrolysergol through different routes. This new process is directed to a quick and economical synthesis procedure that involves three steps.
This invention relates to a process for preparing pergolide from 9,10-dihydrolysergol via an acylamide intermediate with two alternative routes. The process comprises reacting 9,10-dihydrolysergol with an acid anhydride at an elevated temperature in the presence of a catalyst to form a triacylated product intermediate; reducing the triacylated product intermediate with a reducing agent in a solvent to form a primary amino alcohol intermediate; and reacting the amino alcohol intermediate with dimethyl disulfide and trialkyl phosphine, aryl phosphine or the polymeric derivatives of phosphine analogs thereof in a polar solvent to obtain pergolide.
The alternative process comprises reacting 9,10-dihydrolysergol with dimethyl disulfide and trialkyl phosphine, aryl phosphine or the polymeric derivatives of phosphine analogs thereof in a polar solvent to form a methylsulfide intermediate; reacting the methylsulfide intermediate with an acid anhydride at an elevated temperature in the presence of a catalyst to form a diacylated amide intermediate; and reducing the diacylated amide intermediate with a reducing agent in a solvent to obtain pergolide.
As used herein, Me is methyl; Et is ethyl; Pr is propyl; Bu is butyl; and Ms is mesyl.
The process for preparing pergolide of the invention comprises the following steps:
(a) reacting 9,10-dihydrolysergol (1) with an acid anhydride at an elevated temperature in the presence of a catalyst to form the corresponding triacylated product (5);
(b) reducing the triacylated product (5) with a reducing agent in a solvent to form the corresponding primary amino alcohol (6); and
(c) reacting the amino alcohol (6) with dimethyl disulfide and a trialkyl phosphine, aryl phosphine or the polymeric derivatives of phosphine analogs thereof, in a polar solvent to form the pergolide product (4).
The reaction procedure is shown in scheme III: 
Step (a) of this process refers to acylation-dealkylation. Gerszberg et al. reported (S. Gerszberg et al. Tet. Lett. 1973 (15), 1269-1272) that acylation-dealkylation of a few simple tertiary amines to the corresponding amides in the presence of an acid anhydride was met with varying degree of success (18-62% yield).
The starting material, 9,10-dihydrolysergol, can be prepared according to the process disclosed in the afore-mentioned U.S. Pat. No. 4,166,182 or any method known in the state of the art.
For step (a) of this process, the suitable acid anhydride has the formula of (Rxe2x80x2CO)2O wherein Rxe2x80x2 is C1-C4 alkyl, i.e. the acid anhydride can be selected from the group consisting of acetic anhydride, propionic anhydride, butyric anhydride, and pentanoic anhydride. For acylation-dealkylation, the excess of the acid anhydride is used to ensure the completion of tri-acylation of 9,10-dihydrolysergol to the corresponding triacylated product.
The acylation-dealkylation is conducted at an elevated temperature, preferably at the refluxing temperature of the reaction mixture, more preferably in the range of 100xc2x0 C. to 200xc2x0 C., normally for 24-60 hours. The catalyst for acylation-dealkylation is preferably selected from sodium iodide (NaI) and dimethylaminopyridine (DMAP), more preferably NaI.
The acylation-dealkylation can be optionally conducted in the presence of a solvent for the modification of the reaction, but preferably without a solvent. The solvents suitable for the reaction can be highly polar solvents, such as those disclosed in the afore-mentioned U.S. Pat. No. 5,463,060, preferably 1-methyl-2-pyrolidinone and the related six-ring compounds thereof.
Step (b) of this process refers to a reduction reaction. The suitable reducing agent is a metal hydride, preferably lithium aluminum hydride (LAH) and Vitride(copyright), more preferably LAH. The reaction temperature is not critical. Normally, the reduction is conducted at a temperature in the range of xe2x88x9230xc2x0 C. to the refluxing temperature of the reaction mixture, preferably in the range of 0xc2x0 C. to 80xc2x0 C., more preferably in the range of 0xc2x0 C. to room temperature. The reduction is conducted in the presence of an ethereal solvent, preferably tetrahydrofuran (THF).
Step (c) of this process refers to sulfide formation. An excess of dimethyl disulfide and a large excess of trialkyl phosphine, aryl phosphine or the polymeric derivatives of phosphine analogs thereof are normally used to achieve the formation of a methyl sulfide intermediate. In sulfide formation, the trialkyl phosphine used has the formula of R3P, wherein R is (CH2)n and n is 1-6. The aryl phosphine used has the formula of Ar3P, wherein Ar is phenyl or substituted phenyl. The reaction temperature is not critical. Normally, the sulfide formation can be conducted at a temperature in the range of 0xc2x0 C. to 150xc2x0 C. The polar solvents suitable for the sulfide formation are preferably dimethyl formamide (DMF) and dimethylsulfoxide (DMSO), more preferably DMF.
One of the preferred embodiments of this process comprises the following steps:
(a) reacting 9,10-dihydrolysergol (1) with propionic anhydride and sodium iodide at a temperature of about 160xc2x0 C. to form the corresponding propionamide (5a);
(b) reducing the propionamide (5a) by lithium aluminum hydride (LAH) in tetrahydrofuran (THF) at room temperature to form the corresponding primary amino alcohol (6a); and
(c) reacting the amino alcohol (6a) with an excess of dimethyldisulfide (Me2S2) and a large excess of tributylphosphine (Bu3P) in dimethyl formamide at a temperature of about 90xc2x0 C. to obtain the pergolide product (4).
The reaction procedure is shown in scheme IV: 
The alternative process for preparing pergolide of the invention comprises the following steps:
(a) reacting 9,10-dihydrolysergol (1) with dimethyl disulfide and a trialkyl phosphine, aryl phosphine or the polymeric derivatives of phosphine analogs thereof, in a polar solvent to form the corresponding methyl sulfide (7);
(b) reacting the methyl sulfide (7) with an acid anhydride at an elevated temperature in the presence of a catalyst to form the corresponding diacylated amide intermediate (8); and
(c) reducing the diacylated amide (8) with a reducing agent in a solvent to obtain the pergolide product (4).
The reaction procedure is shown in scheme V: 
Step (a) of this process refers to sulfide formation. The starting material, 9,10-dihydrolysergol, can be prepared according to the process disclosed in the aforementioned U.S. Pat. No. 4,166,182 or any method known in the state of the art. An excess of dimethyl disulfide and a large excess of trialkyl phosphine, aryl phosphine or the polymeric derivatives of phosphine analogs thereof are normally used to ensure the completion of sulfide formation. The trialkyl phosphine has the formula of R3P, wherein R is (CH2)n and n is 1-6. The aryl phosphine has the formula of Ar3P wherein Ar is phenyl or substituted phenyl. The reaction temperature is not critical. Normally, the sulfide formation can be conducted at a temperature in the range of 0xc2x0 C. to 150xc2x0 C. The polar solvents suitable for the sulfide formation are preferably dimethyl formamide (DMF) and dimethylsulfoxide (DMSO), more preferably DMF.
Step (b) of this process refers to acylation-dealkylation. Gerszberg et al. reported (S. Gerszberg et al. Tet. Lett. 1973 (15), 1269-1272) that acylation-dealkylation of a few simple tertiary amines to the corresponding amides in the presence of acid anhydride was met with varying degree of success (18-62% yield).
In step (b) of this process, the acid anhydride used has the formula of (Rxe2x80x2CO)2O, wherein Rxe2x80x2 is C1-C4 alkyl, i.e. the acid anhydride can be selected from the group consisting of acetic anhydride, propionic anhydride, butyric anhydride, and pentanoic anhydride. For acylation-dealkylation, an excess of the acid anhydride is used to ensure the completion of di-acylation to form a di-acylamide intermediate.
The acylation-dealkylation is conducted at an elevated temperature, preferably at the refluxing temperature of the reaction mixture, more preferably in the range of 100xc2x0 C. to 200xc2x0 C., normally for 24-60 hours. The catalyst used is preferably selected from sodium iodide (NaI) and dimethylaminopyridine (DMAP), more preferably NaI.
The acylation-dealkylation can be optionally conducted in the presence of a solvent for modification of the reaction, but preferably without a solvent. The solvents suitable for the reaction can be highly polar solvents, such as those as disclosed in the afore-mentioned U.S. Pat. No. 5,463,060, preferably 1-methyl-2-pyrolidinone and the related six-ring compounds thereof
Step (c) of this process refers to a reduction reaction. The suitable reducing agent is a metal hydride, preferably lithium aluminum, hydride (LAH) and Vitride(copyright), more preferably LAH. The reaction temperature is not critical. Normally, the reduction is conducted at a temperature in the range of xe2x88x9230xc2x0 C. to the refluxing temperature of the reaction mixture, preferably in the range of 0xc2x0 C. to 80xc2x0 C., more preferably in the range of 0xc2x0 C. to room temperature. The reduction is conducted in the presence of an etheral solvent, preferably tetrahydrofuran (THF).
One of the preferred embodiments of this alternative process comprises the following steps:
(a) reacting 9,10-dihydrolysergol (1) with an excess of dimethyl disulfide (Me2S2) and a large excess of tributylphosphine (Bu3P) in dimethyl formamide at a temperature of about 90xc2x0 C. to form the corresponding methylsulfide (7a);
(b) reacting the methylsulfide (7a) with propionic anhydride in the presence of sodium iodide at a temperature of about 160xc2x0 C. to form the corresponding di-propionamide (8a); and
(c) reducing the di-propionamide (8a) with lithium aluminum hydride (LAH) in tetrahydrofuran (THF) at room temperature to obtain the pergolide product (4).
The reaction procedure is shown in scheme VI: 